AI Article Synopsis
- Amino acid metabolism disturbances in Huntington's disease (HD) contribute to severe malnutrition in patients.
- The disease is linked to an expansion of polyglutamine repeats in the huntingtin protein (Htt), affecting various cellular functions like transcription and motor skills.
- The study reveals that oxidative stress disrupts the function of the master regulator ATF4, and antioxidant supplementation can restore its response, highlighting a connection between amino acid balance, oxidative stress, and cellular toxicity.
Article Abstract
Disturbances in amino acid metabolism, which have been observed in Huntington's disease (HD), may account for the profound inanition of HD patients. HD is triggered by an expansion of polyglutamine repeats in the protein huntingtin (Htt), impacting diverse cellular processes, ranging from transcriptional regulation to cognitive and motor functions. We show here that the master regulator of amino acid homeostasis, activating transcription factor 4 (ATF4), is dysfunctional in HD because of oxidative stress contributed by aberrant cysteine biosynthesis and transport. Consistent with these observations, antioxidant supplementation reverses the disordered ATF4 response to nutrient stress. Our findings establish a molecular link between amino acid disposition and oxidative stress leading to cytotoxicity. This signaling cascade may be relevant to other diseases involving redox imbalance and deficits in amino acid metabolism.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4978294 | PMC |
| http://dx.doi.org/10.1073/pnas.1608264113 | DOI Listing |
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